AB0038 DUAL TARGETING PEPTIDE RLS-0071 REDUCES AND INHIBITS MYELOPEROXIDASE (MPO) IN HEALTHY HUMAN VOLUNTEER
Authors: P. Kumar, K. Cunnion, N. Krishna, U. Thienel, P. Hair, J. Goss, C. Gabriel
Journal: Annals of the Rheumatic Diseases (2022)

Background RLS-0071-101 was a first in human clinical trial to evaluate safety of the peptide RLS-0071 in healthy volunteers in a single ascending dose and multiple ascending dose format. RLS-0071, previously referred to as Peptide Inhibitor of Complement C1 (PIC1) is a dual-targeting peptide being developed for clinical use to moderate humoral and cellular inflammation via inhibition of complement activation and neutrophil effectors including myeloperoxidase (MPO) and Neutrophil extracellular trap formation (NETosis). 1,2 Humans that are otherwise asymptomatic are considered at risk for cardiovascular complications if they have a plasma MPO level of &gt; 420 pmol. 3 A post hoc analysis of plasma samples from subjects participating in RLS-0071-101 identified an individual with mildly elevated baseline MPO level (142 pmol/L). Objectives Evaluate if RLS-0071 dosing would change MPO level or activity in a subject with elevated baseline MPO. Methods Frozen plasma samples prepared from blood collected by venipunture into K2EDTA tubes (BD) was utilized to determine MPO quantity and activity levels. MPO quantity in the plasma was analyzed using a human MPO ELISA kit (BMS2038INST, Invitrogen) and MPO activity within the plasma was analyzed using a fluorescence-based myeloperoxidase assay kit (K745-100, BioVision). Results Upon screening 54 subjects from RLS-0071-101 we identified one individual with a mildly elevated MPO level at baseline, a 21-year-old white female with BMI of 21.7. The subject received 9 intravenous infusions of RLS-0071 each at a dose of 10 mg/kg. Her vital signs and body temperature remained normal throughout the study and the only blood laboratory abnormality were a mildly low plasma protein concentration of Day 2 and Day 4 which was noted both among recipients of the peptide and placebo subjects. Analysis of MPO blood concentrations demonstrated a mildly elevated baseline plasma MPO concentration that decreased after multiple doses of RLS-0071 with partial recovery to baseline 24 hours after cessation of dosing. MPO activity analyzed using a fluorescence-based myeloperoxidase assay kit demonstrated an elevated baseline plasma MPO activity level that decreased after multiple doses of RLS-0071 with partial recovery after 24 hours. Conclusion These results suggest promise for RLS-0071 to reversibly moderate plasma MPO activity and potentially affect MPO-mediated diseases including acute coronary syndrome (ACS), atheromatous plaque vulnerability and auto immune conditions.4,5,6,7. References [1]Sharp, Julia A., et al. “Peptide inhibitor of complement c1, a novel suppressor of classical pathway activation: mechanistic studies and clinical potential.” Frontiers in immunology 5 (2014): 406. [2]Hair, Pamela S., et al. “Inhibition of myeloperoxidase activity in cystic fibrosis sputum by peptide inhibitor of complement C1 (PIC1).” PLoS One 12.1 (2017): e0170203. [3]Tang WH, Wu Y, Nicholls SJ, Hazen SL. Plasma myeloperoxidase predicts incident cardiovascular risks in stable patients undergoing medical management for coronary artery disease. Clin Chem. 2011;57(1):33-9. [4]Malle, E.; Marsche, G.; Panzenboeck, U.; Sattler, W. Myeloperoxidase-mediated oxidation of high-density lipoproteins: Fingerprints of newly recognized potential proatherogenic lipoproteins. Arch. Biochem. Biophys., 2006, 445 (2), 245-255. [5]Nurcombe, H. L.; Bucknall, R. C.; Edwards, S. W. Activation of the neutrophil myeloperoxidase-H2O2 system by synovial fluid isolated from patients with rheumatoid arthritis. Ann. Rheum. Dis., 1991, 50 (4), 237-242 [6]Malle, E.; Buch, T.; Grone, H. J. Myeloperoxidase in kidney disease. Kidney Int., 2003, 64 (6), 1956-1967. [7]Nicholls, S. J.; Hazen, S. L. Myeloperoxidase and cardiovascular disease. Arterioscler., Thromb., Vasc. Biol., 2005, 25 (6), 1102- 1111. Disclosure of Interests Parvathi Kumar Shareholder of: I have stock options available, Consultant of: Served as a consultant for ReAlta life Sciences INC from April- July 2020, Employee of: I am employed by ReAlta Life Sciences, Kenji Cunnion Shareholder of: Shareholder of ReAlta life sciences, Employee of: ReAlta Life Sciences, Neel Krishna Employee of: I am an employee of ReAlta Life Sciences., Ulrich Thienel Shareholder of: Shareholder of ReAlta and JNJ, Employee of: ReAlta Life Sciences, Pamela Hair Employee of: ReAlta Life Sciences, Jessica Goss Employee of: ReAlta Life Sciences, Christos Gabriel: None declared